Syringaresinol Alleviates Early Diabetic Retinopathy by Downregulating HIF‐1α/VEGF via Activating Nrf2 Antioxidant Pathway

Scope Early diabetic retinopathy (DR) is characterized by chronic inflammation, excessive oxidative stress, and retinal microvascular damage. Syringaresinol (SYR), as a natural polyphenolic compound, has been proved to inhibit many disease progression due to its antiinflammatory and antioxidant properties. The present study focuses on exploring the effect of SYR on hyperglycemia‐induced early DR as well as the underlying mechanisms. Methods and results Wild‐type (WT) and nuclear factor erythroid 2‐related factor 2 (Nrf2)‐knockout C57BL/6 mice of type 1 diabetes and high glucose (HG)‐induced RF/6A cells are used as in vivo and in vitro models, respectively. This study finds that SYR protects the retinal structure and function in diabetic mice and reduces the permeability and apoptosis of HG‐treated RF/6A cells. Meanwhile, SYR distinctly mitigates inflammation and oxidative stress in vivo and vitro. The retinal microvascular damages are suppressed by SYR via downregulating hypoxia‐inducible factor‐1α (HIF‐1α)/vascular endothelial growth factor (VEGF) pathway. Whereas, SYR‐provided protective effects are diminished in Nrf2‐knockout mice, indicating that SYR improves DR progression by activating Nrf2. Similarly, SYR cannot exert protective effects against HG‐induced oxidative stress and endothelial injury in small interfering RNA (siRNA)‐Nrf2‐transfected RF/6A cells. Conclusion In summary, SYR suppresses oxidative stress via activating Nrf2 antioxidant pathway, which ameliorates retinal microvascular damage by downregulating HIF‐1α/VEGF, thereby alleviating early DR progression. Schematic diagram of the protective effect of syringaresinol (SYR) against retinal microvascular damage of DR in a manner dependent on Nrf2 antioxidant pathway activation. SYR suppresses oxidative stress via activating Nrf2/HO‐1/SOD2 pathway, which ameliorates retinal vascular damage by downregulating HIF‐1α/VEGF pathway, ultimately alleviating DR progression. In addition, SYR controls gliosis and inhibits neuronal apoptosis induced by hyperglycemia.